Process for making bismuth tartrates and product produced thereby



I ration.

Patented PHILIP ADOLPH KOBER, or EVANSTON, ILLrnoIs, Assrenoaro a. D. sEARLE & 00., or cnrcaeo, rumors, A ooaronarron or rumors- PROCESS FOR MAKING IBISMUTH TARTRATES AND PRODUCT PRODUCED THEREBY.

No Drawing.

This invention relates to improvements in the manufacture and composition of bismuth tartrates, especially intended for the treatment of syphilis.

The use of bismuth therapy in syphilis since its introduction in France a few years ago has gradually grown so that it has become a valuable addition to our regular'antisyphilitic chemotherapeutic agents, the arsenicals.

L. E. Warren of the Chemical Laboratories ofthe American Medical Association, (Journ. Amer. Med. Ass. 84, 1067, 1925) writing under the title What is the composition of bismuth tartra-tes used in the treatment of syphilis, stated as part of his summary that the fact that the bismuth content inthe various bismuth preparations-' the satisfactory as well as the unsatisfac toryis within such a wide range (31-73%) emphasizes the necessity for clinicians to inquire carefully concerning the. composition of the bismutli products they use, particularlyin reference to the bismuth content,-

before making reports concerning the alleged efi'ectiv'eness of this, that or the other prepa- This statement was based upon analyses of practically all, seven in number, of the bismuth preparations on the market.

Theoretically and actually found, there are many difierent compounds of bismuth and tartaric acid. Of the water soluble preparations which are probably more efiec tive on account of speedier absorption and greater enetration, all of them also containin a dition to bismuth and tartaric acid, alkali metals, either sodium or potassium or both. Ordinary bismuth salts of tartaric acid have too great a tendency to hydrolyze into insoluble bismuth oxide or basic salts to be desirable for syphilitic treatment.

.Theretore the more firmly the bismuth is bound tothe tartaric acid, in the form of a complex salt, the greater efiicacy can be expected as the-bismuth must remain in the form of a. soluble organic complex long enough to allow absorption from the site of injection and to be distributed throughout the body by means of the blood stream.

Application filed May 28,

1926. Serial No. 112,398;

Chemical tests. show that the most firmly bound. bismuth compounds of those heretofore isolated, are the tri-bismuth alkali tartrates, of which the only known example is potassium tri-bismuth tartrate. The following formula has been assigned to this com pound:

'O0-Bi=i0 H- OBi=0 H- O-Bi=0 4-H=o O Anhydrous With water of 72. 8% hydration Bismuth a Bismuth This compound and its preparation was first described by Rosenhei'm and Vogelsang (Zeitschrift fiir Anorg. Chem. 48, 205, (1906)) and has been 011' the market and used clinically both here and abroad.

So far as I am aware no similar sodium product has been prepared, although theoretically it might have some advantages over the potassium compound. To manyworkers in pharmacology and medicine, potassium compounds of therapeutic agents are not so desirable as the corresponding sodium compounds. On this subject the'U.S.-

Dispensatory (twentieth edition) states on page 912 that while thepresence of a certain amount of potassium in the bloodis essential for vital activity, a' very slight in crease in its percentage has a deleterious influence on many organs. The injection of a potassium salt into the circulation weakens the contractile power of all muscle fibers but afi'ects' especially the heart and blood vessels. It also exercises a marked depressant action upon the central nervous system, including the spinal cord, brain and medulla. Although the depressant action of potassium is strong when injected directly into, the blood stream, when-taken by the mouth it exercisesvery little influence upon the circulation. This is due to the fact that it is excreted by the kidneys so rapidly that it cantartrat'e" seemed desirable and of value. No

method was'favailable in the literaturev which described the'isolationof such a sodium compound; Bosenheim and Vogelsang attempted to isolate the sodium compound but they stated-it would not crystallize out similarly to the potassium compound. Klau'der makes the statement that the sodium salt is unstable which indicates in the light of the work report'e'd'here that the sodium compound had not been successfully isolated, or at least a sodium compound similar to the one de- Tcribed in' this disclosure had not been isoated.

I 'On'considering the method of Rosenheim J and Yogelsang, which consists in digesting bismuth subuitrate with tartaric acid and an excess of alkali whileheating, I came to the conclusion, that from thermo-dynamicreasoning, the reaction ought to be conducted in the cold or at least without heating.

Furthermore since the nitrate group does not enter i'nto' the composition of the compound desired, its presence. may interfere with the reaction. For these reasons I tried the reaction with a slight excess of sodium hydroxide in the cold, using bismuth. hy-

droxide as a source-of bismuth and shaking with a ,mechanical shaker. The bismuth hydroxide at first dissolved fairly rapidly,

- but.soon .i t dissolved more and more slowly.

Howeyefianumber of experiments showed that the longenI shook the mixture, the more'bismuth hydroxide dissolved. At the end ofiabout 144 hours (6 days about) the mixtu're' seemed to come to an equilibrium and no more bismuth hydroxide seemed to dissolve. On filtering'I had in solution, of cours'e, a sodium bismuth tartrate. A few experiments with small portions of the filtrate soon showed that a half volume of 95%alcohol gave me a copious yield of P116- cipitate. The precipitate after .washing w1th'1 5 0% alcohol several times to remove the mother liquor and finally-with 95% al-.

cohol'and drying in the air at room temperature gave a water soluble powder containing 72.9% of bismuth'and 4.6% of water of hydration, or for an anhydrous substance 76.4% of bismuth, Since the anhydrous sodium tri-bismuth tartrate could not contain more than 74.2% of bismuth, it was evi dent that this'preparation contained more than three molecules of bismuth. The the'o retical per cent for bismuth and water for sodium tetra-bismuth tartrate and sodium I i tri-bisniuth tartrate is as follows:

' From this data I was forced to the conclusion that this sodium tartrate compound was sodium tetra-bismuth tartrate and I have tentatively assigned the following formula to it.

Sodium tetra-bismuth tai'trate 77.1% Bi Potassium tetra-bismuth tartrate 75.8% K

- If these findings and c'onclusions with the sodium compound were correct, then it ought to be possible to get a potassium compound of similar composition with even more bismuth content than any found on the-market, since most of them approximate inbismuth content that of a tri-bismuth tartrate.

On substituting potassium hydroxide for sodium hydroxide in the method developed for the sodium compound, I had no difli cultyin getting a fair yield on the first trial using otherwise the exact technic as I did for the sodium process. It is probable that by using more suitable proportions of alcohol, since the solubilities of the. two substances undoubtedlydiifer, a greater yield would have been obtained. However, the analytical data; agree with the theory for a tetra-bismuth tartrate even more. closely than did the sodium compound:

. lHzO 21320 Anhy- Potassium compound drous 31% 11.0% 121% H:O% Bi% Theory for tri-bismuth tartrate. 72.9 2.05 71.4 4.02 70.0 Actually found 75.8 2.76 73.8 Theory for tetra-bismuth tartra e 8 3.16 73 3 then dissolve. Accurate solubility determi- Inc nations have not yet been made, indications are that the solubility at room temperatures Solutions of these tetra-bismuth tartrates are alkaline in harmony with the formula, and so far as we know are perfectly stable. The alkalinity. can be decreased by titrating with N/lO sulphuric acid, using phenolphthalein as an indicator, to a hydrogen ion concentration of 'a P 8. l8.6, at which point the solutions up to seem stable indefinitely. Heating such solutions to 70 C. for 45 minutes seems to cause no change whatever, while heating5 minutes at100 (I. produced only a very slight cloud and a slight increase in alkalinity, butwhich'on cooling slowly returned to its original state.

The alkalinity can be also decreased by absorption of iodine, with the formation of colorless solutions of iodides and iodates of theitetra-bismuth tartrates, which also seem stable at room temperatures.

On adding a gram equivalent of acid to 1 solutions of tetra-bismuth tart-rates a precipitate is produced, which redissolves in an equivalent amount of alkali, indicating that the precipitate is a tetra-bismuth tartrate base. Large excess of acids decompose the base so that it does not .redissolve in an equivalent amount of alkali. This base is very gelatinous and seems to -be close to a permanent suspensoid. Ralziss, Severac and W1n1cov (Amer.

' Journ. of Olin. Med. August 1923) quote Sazerac and Levaditi, who werevthe first to study bismuth tartrates as curative agents for syphilis, as stating that their sodium and potassium bismuth tartrate killed'white rats when 5 milligrams per kilogram of animal was injected intravenously. Raiziss and associates found their potassium tribismuth tartrate was tolerated up to 10 milligrams per kilogram, but killing at 15 milligrams per kilogram. Our prehminarymesults with white rats indicate that these tetra-bismuth tartrates are considerably less toxic being tolerated when injected intravenously up to about-'25 milligrams per kilogram of body weight.

The r sults of my investigation as above described confirm my belief that the temperature at which the reaction between the alkali and the bismuth compound is carried out is important in determining whether the tri-bismuth tartrates or the tetra-bismuth tartrates will be formed. One of the essential features or my process of producing the new is carried on that it shall be maintained be- I low a point where substantial amounts of tribismuth tartrates are formed.

to about 1500 cc. Then with rapid stirring 300 cc. of saturated sodium hydroxide (50%) were added to precipitate the bismuth as hydroxide in a finely divided condition.

upon a suction filter, washed and resuspended in water, filtered, "washed with distilled water three ormore times until all of the mother liquor had been removed.

The preclpitate was then filtered"- Into a liter bottle or flask were'weighed. I l

25.0 grams of tartaric acid and 7 5 cc. of distilled water added. Then 28 cc. of saturated'sodium hydroxide (50%) were added withstirring and cooling. .When the liquid had cooled to 1415 C. the bismuth hydroxide, prepared as described above was added and after stoppering the bottle or flask securely, the mixture was shaken on a 7 mechanical shaker for from one hour to two hours, at three hour intervals during the first day. This shaking was repeated two or more times a day for 6 to 7.days. Longer standing or shaking caused no harm, but the amount of bismuth hydroxide ,dissolved by the alkaline tartrate solution was but slightly increased over the amount dissolved during the first six days. Attempts to shorten the period by heating decreas'edthe amount and purity of the yield.

The mixture atthe end of six days was filtered through a porous glass Buchner suction filter or through a hard filter paper.

'After'washing the undissolved bismuth 'hydroxide with 50 cc. 'of distilled water, the total filtrate equalled 350 cc.

not

On adding 175 cc. of 95% alcohol to the I filtrate withstirring, a copious precipitate was obtained, which was filtered on a Buchn'er funnel with suction, washed and sus pended in 100 'cc. of 50% alcohol, filtered and washed, ,resuspended, filtered and washed with 95% alcohol three or four times or until the filtrate was neutral to litmus paper. After drying 'at room temperature for several days, the yield was in the neigh borhood of grams or 89%. On substi -tuting the sameproportion of potassium hy= droxide for sodium hydroxide, the yieldwas about 30%.

That these tetra-bismuth tartrates have never before been isolated is indicated by the high content ofbismuth, by the stability of the aqueous solutions, and by the rela tively low toxicity, to ofthat of the products made by Raiziss and A; of that.

made by Sazerac' and Levaditi, the French originators of-bismuth therapy; I

Since in'this disclosurevl have shown how to form thesenew salts or compounds easily, and therefore have demonstrated the fundamental conditions under which such comular application above mentioned. Accord-' and tartaric acid at a temperature promoting the formation of a tetra-bismuth tar-' pounds are made, it will be understood that other alkalies, such .as ammonium and lithium, etc., can be used 'to produce the correspending-compounds, or that any combination o'gt'alkalies may be used to replace a single alkali, producing a bismuth tartrate containing in its composition two or more diiferent alkalies. Furthermore since the base containing four atoms of bismuthto every molecule of tartaric acid can be isolated, by simple neutralization and otherwise, and will dissolve in a gram equivalent of alkali, alsolubility greatly in excess of that shown by the bismuth coinpoundsheretofore considered suitable for such purpose, it is particularly well adapted for use in medicine generally as well as for the particingly, the invention is to be given a broad interpretation and the composition and process are not to be limited in proportions or procedure other than as indicated in the appended claims.

What isclaimed is:

1. A process for making bismuth tartratesv which consists in treating a basic bismuth compound with analkali and tartaric acld at not exceeding normal room temperature. '2; A process of making bismuth tartrates which-consists in treating a basic bismuth compound with an alkali metal hydroxlde trate, but suificiently low to prevent the for- ;mation of substantial amounts of tri-bis v muth tartrates.

3. A process for making bismuth tartrates which-consists in treating a basicbismuth compound with an alkali and tartaric acid temperature.

at not exceeding normal room temperature, separating off the'excess of bismuth salts,

and precipitating the bismuth tartrate'with- 6. A process for making a sodium bismuth tartrate comprising treatlng a basic bismuth 'taric acid at not exceed1ng normal room compound with sodium hydroxide and tartemperature, separating ofi the excess bisbismuth tartrate with alcohol, substantially as described. Y

7. A process for making an alkali metal muth salts, and precipitating the sodium bismuth tartrate comprising treating a basic bismuth compound with an alkali metal hy droxide and tartaric acid at not exceeding normal room temperature. v

8. A process of makmg an alkali metal bismuth tartrate comprising treating bismuth hydroxide with? an alkali metal hydroxide and tartaric acid -while maintaining the temperature at not exceeding normal room temperature.

9. A process for making an alkali metal bismuth tartrate comprising treating a basic bismuth compound with an alkali metal hydroxide and tartaric acid at not exceeding normalroom temperature, separating o'flf the excess bismuth salt, and precipitating the alkali metal'bismuth tartrate with alcohol,-

substantially. as described.

10. A process for making alkali metal tetra-bismuth tartrates comprising treating a basic bismuth compound with an alkali metal hydroxide and tartaric acid at n0t exceeding normal room temperature. 11..A process of making alkali metal tetra-bismuth tartrates .which comprises treating bismuth hydroxides Witha solution of an alkali metal hydroxide and tartaric acid at approximately 1415 C.

12. A process tor making an alkali metal tetra-bismuth tartrate comprising treating a basic bismuth compound with an alkali and tartaric acid at not exceeding normal room temperature, separating ofi-the excess bismuth salts, and precipitating the alkali metal tetra-bismuth tartrate with alcohol, substantially as described.

13.-.A soluble bismuth tartrate; having over 72.9% ofbismuth.

'14. A soluble alkali metal bismuth tartrate. having over 7 2.9% of bismuth.

15. An alkali metal bismuth tartrate hav- 1 ing four atoms of bismuth for. every molecule of tartaric acid. i

16. A bismuth tartrate havlng four atoms of bismuth for every molecule of tartaric acid.

17. A sodium bismuth tartrate four atoms of bismuth to every molecule of tartaric acid? In testimony whereof, I have signed my name to this specification this twenty-second day of May, 1926. 4

PHILIP ADOLPH KOBER.

having 

